The role of signaling molecule AIP1 in pathological angiogenesis

描述（由申请人提供）：血管生成，即新血管形成的过程，涉及许多生理和病理情况，如缺血、糖尿病、动脉粥样硬化和癌症。已经确定了几种血管生成途径是成人发育性血管生成和血管适应性反应所必需的。已经认识到某些在病理（例如炎症和缺血）中起重要作用的基因不参与生理性血管生成。然而，发病机制相关的血管生成的基础机制还没有得到很好的理解。我们假设，病理性血管生成相关基因的表达，激活或与有效的血管生成途径，在病理刺激，它们调节出生后的血管生成反应和组织重塑。我们已经确定了AIP 1，一种新的信号蛋白作为一种有效的抑制剂，在病理性血管生成，但不发育。在本申请中，我们提出了以下具体目标来定义AIP 1在炎性血管生成中的作用：1）定义AIP 1抑制VEGFR 2信号传导的机制。我们将检查AIP 1是否与VEGFR 2的活性形式结合，延迟VEGFR 2的内吞作用和/或辅助磷酸酶向VEGFR 2的募集以减弱VEGFR 2依赖性血管生成信号。2)确定AIP 1如何抑制NF-κ B依赖性炎症，以及病理性血管生成中AIP 1表达的调节。我们将确定AIP 1如何通过其C-末端CC/LZ结构域与NEMO竞争RIP 1结合，破坏IKK复合物的形成，以及JAK 2/Bmx-SOCS 3如何介导病理性血管生成过程中AIP 1的磷酸化和降解。3)确定AIP 1在炎症诱导的血管生成中的EC特异性功能。我们将使用EC特异性AIP 1- KO小鼠和EC特异性AIP 1转基因小鼠确定小鼠模型中的炎症反应和病理性血管生成。我们将在这些模型中测试AIP 1衍生肽的潜在治疗作用。

DESCRIPTION (provided by applicant): Angiogenesis, the process of new blood vessel formation, is involved in many physiological and pathological settings such as ischemia, diabetes, atherosclerosis and cancer. Several angiogenic pathways have been identified to be essential for developmental angiogenesis and vascular adaptive responses in adult. It has been recognized that certain genes that play important roles in pathological (e.g, inflammation and ischemia) are not involved in physiological angiogenesis. However, the underlining mechanisms for the pathogenesis-associated angiogenesis are not well understood. We hypothesize that pathological angiogenesis-associated genes are expressed, activated or associated with potent angiogenic pathways in response to pathological stimuli where they modulate postnatal angiogenic responses and tissue remodeling. We have identified AIP1, a novel signaling protein as a potent inhibitor in pathological but not developmental angiogenesis. In this application we propose the following specific aims to define the role of AIP1 in inflammatory angiogenesis: 1) Define the mechanism by which AIP1 inhibits VEGFR2 signaling. We will examine if AIP1 binds to an active form of VEGFR2, delaying VEGFR2 endocytosis and/or assisting recruitment of phosphatase(s) to VEGFR2 to attenuate VEGFR2-dependent angiogenic signaling. 2) Determine how AIP1 inhibits NF-kB-dependent inflammation, and the regulation of AIP1 expression in pathological angiogenesis. We will determine how AIP1 via its C-terminal CC/LZ domain competes with NEMO for the RIP1 association, disrupting IKK complex formation, and how JAK2/Bmx-SOCS3 mediates AIP1 phosphorylation and degradation during pathological angiogenesis. 3) Define the EC-specific functions of AIP1 in inflammation-induced angiogenesis. We will determine inflammatory responses and pathological angiogenesis in mouse models using EC-specific AIP1- KO mice and EC-specific AIP1 transgenic mice. We will test the potential therapeutic effects of AIP1-derived peptides in these models.